October 26, 2013. http://dx.doi.org/10.1016/. S0140-6736(13)61941-8.
Randomised controlled trials of the eff ect of stopping treatment are rare, but in The Lancet Josef Smolen and colleagues1 report results showing that it is possible to stop a risky and expensive treatment for many patients with rheumatoid arthritis once an initial response has been obtained. Newly diagnosed adult patients were treated fi rst with either methotrexate plus placebo (n=517) or methotrexate plus the biological drug adalimumab (n=515), a fully human monoclonal antibody that binds to tumour necrosis factor (TNF), preventing it from activating TNF receptors.
More patients in the methotrexate plus adalimumab group (207 of 466 [44%] completers, 40% of patients randomised) attained a predefi ned low disease activity target (28-joint disease activity score with C-reactive protein [DAS28] <3·2) at weeks 22 and 26 compared with methotrexate alone (112 of 460 [24%] completers, 22% of patients randomised).1,2
Patients with low disease activity in the methotrexate plus adalimumab group were then randomly allocated to continue this treatment, or to switch to methotrexate plus placebo. Patients who achieved the target with methotrexate monotherapy continued that regimen. The primary endpoint was a composite measure of DAS28 of less than 3·2 at week 78 and radiographic non-progression from baseline to week 78, compared between adalimumab-continuation and methotrexatemonotherapy, and was achieved by more patients in the adalimumab-continuation group (73 of 105 [70%]) than the methotrexate-monotherapy group (61 of 112 [54%]; mean diff erence 15% [95% CI 2–28]). However, importantly, outcomes for clinical symptoms and radio graphic progression were assessed in all groups at week 78—by which time patients who withdrew adalimumab mostly maintained their good responses.
This study—the OPTIMA trial—was very large (more than 1000 patients at 161 sites), and in our opinion excellently done, properly analysed, and appropriately interpreted. And yet we fi nd ourselves interpreting the result in a wider context than the investigators, who comment that withdrawal of the biological agent might be an option for most patients with early rheumatoid arthritis who achieve initial disease control. We think this study raises three other questions: did the patients need to take biological therapy in the fi rst place? Was there another treatment eff ect hidden within the trial results? And how should the cost-eff ectiveness of biological therapy be calculated?
The initial control group of this study was methotrexate plus placebo, but scientifi c literature on the treatment of newly diagnosed rheumatoid arthritis, some reported since OPTIMA was designed, very strongly suggests that methotrexate monotherapy is an inadequate and old fashioned therapy. Combination therapy, particularly including glucocorticoids (which we advocate in our practice) would be a more appropriate comparator group,3–6 and some would argue that a so-called treat-to-target policy of dose escalation would be even more eff ective (although its cost-eff ectiveness has not yet been shown).6,7 Indeed, these combination therapies have been shown to produce treatment eff ects very similar to biological therapies. We would no longer off er monotherapy with methotrexate to our patients except in rare circumstances. Trial comparisons should compare new treatments to the best available alternative, but many do not. Showing that a new treatment is better than an old treatment that has been superseded does not add useful knowledge.
Other treatments were used in OPTIMA; in particular, more than 40% of patients were treated with glucocorticoids during the fi rst 26 weeks of the study. As is common in most trial reports, the random allocation of patients meant that roughly equal proportions of patients were taking glucocorticoids in each group, and hence the trial interpretation often ignores this aspect of treatment. But the evidence shows an additional eff ect of glucocorticoids added to other disease modifying therapies,3–6 such as methotrexate. Might it be that the therapeutic benefi ts are also heightened in those patients taking glucocorticoids at the same time as biological therapies? The data from this and other studies of biological therapies should be analysed from this point of view.
How do we estimate the cost-eff ectiveness of
expensive treatments such as biological therapy?
Their cost is an order of magnitude greater than
those of combinations of standard treatment plus
glucocorticoids. In most countries, biological therapy
is only reimbursed when methotrexate and one other
traditional antirheumatic drug have failed. In the UK,
the National Institute for Health and Care Excellence
(NICE) has applied the clinical trial outcomes from
biological therapy to a mathematical model of costs
and benefi ts, resulting in a strict reimbursement rule
compared with many other European countries.8
And even in NICE’s analysis cost-eff ectiveness of
biological agents might be exaggerated, because the
model compares biological agents with methotrexate
monotherapy rather than the more eff ective
combination therapy. In this situation, were healthcare
providers to change the practice for initial
treatment of rheumatoid arthritis on the basis of
OPTIMA, all patients with early rheumatoid arthritis
would receive biological treatment, and less than half
would reach the low disease activity target allowing
them to stop after 6 months. Costs would skyrocket.
At a time of constraint in health-care budgets,
health-care providers should spend their money
wisely, and NICE should reset its economic model
for rheumatoid arthritis to include the outcomes of
modern combination therapy, treatment which it
itself recommends.9 For many patients, the intelligent
use of combination therapy including glucocorticoids
will eliminate the need for early biological therapy.
For patients who do need biological therapy and then
achieve stable low disease activity, the OPTIMA results
suggest it might be reasonable to consider switching
back to non-biological treatment.
We congratulate Smolen and colleagues for tackling
the problem of treating rheumatoid arthritis from a
new standpoint, for showing how a trial of stopping
treatment can be so informative, and for providing
a very useful opportunity for re-evaluating the best
possible role of routine combination therapy in the early
stages of this important disease.
*John R Kirwan, Maarten Boers
University of Bristol Academic Rheumatology Unit, Bristol Royal
Infi rmary, Bristol BS8 2UR, UK (JRK); and Department of
Epidemiology and Biostatistics, VU University Medical Center,
Amsterdam, Netherlands (MB)
We declare that we have no confl icts of interest.
1 Smolen JS, Emery P, Fleischmann R, et al. Adjustment of therapy in
rheumatoid arthritis on the basis of achievement of stable low disease
activity with adalimumab plus methotrexate or methotrexate alone: the
randomised controlled OPTIMA trial. Lancet 2013; published online Oct 26.
2 Kavanaugh A, Fleischmann RM, Emery P, et al. Clinical, functional and
radiographic consequences of achieving stable low disease activity and
remission with adalimumab plus methotrexate or methotrexate alone in
early rheumatoid arthritis: 26-week results from the randomised,
controlled OPTIMA study. Ann Rheum Dis 2013; 72: 64–71.
3 Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Comparison
of treatment strategies in early rheumatoid arthritis: a randomized trial.
Ann Intern Med 2007; 146: 406–15.
4 Möttönen T, Hannonen P, Leirisalo-Repo M, et al. Comparison of
combination therapy with single-drug therapy in early rheumatoid
arthritis: a randomised trial. Lancet 1999; 353: 1568–73.
5 Bakker MF, Jacobs JW, Welsing PM, et al. Low-dose prednisone inclusion in
a methotrexate-based, tight control strategy for early rheumatoid arthritis:
a randomized trial. Ann Intern Med 2012; 156: 329–39.
6 Kirwan JR, Bijlsma JWJ, Boers M, Shea B. Eff ects of glucocorticoids on
radiological progression in rheumatoid arthritis. Cochrane Database Syst Rev
2007; 1: CD006356.
7 Kirwan JR. Combination therapy including glucocorticoids: the new gold
standard for early treatment in rheumatoid arthritis? Ann Intern Med 2012;
8 NICE. Adalimumab, etanercept and infl iximab for the treatment of
rheumatoid arthritis. Technology appraisals, TA 130—issues October, 2007.
http://www.nice.org.uk/TA130 (accessed Sept 25, 2013).
9 National Collaborating Centre for Chronic Conditions. Rheumatoid
arthritis: national clinical guideline for management and treatment in
adults. London: Royal College of Physicians, 2009.